Prenatal exposure to drugs of abuse alters the course of brain development and may have profound and long-lasting effects on behavior in adults. Low doses of cocaine, administered intravenously in pregnant rabbits, results in fetal onset of long-lasting defects in the dendritic growth of pyramidal neurons in dopamine (DA)-rich cortical regions, with accompanying alterations of neurotransmitter-related molecules. Perhaps the most remarkable aspect of prenatal cocaine exposure in this model is the severe reduction in D1 receptor coupling to a G-protein, effectively eliminating D1-Gsalpha mediated responses both prenatally and in adulthood. In this context, we recently discovered developmental defects of a nature similar to the rabbit in the D1 receptor null mouse. This finding supports our hypothesis that cocaine-induced changes in DA signaling initiate a cascade that results in abnormal neuronal development and circuit function in DA-rich regions of the forebrain. Developmental adaptations that occur due to exposure to drugs of abuse prenatally may be distinct from those that may occur when exposed to the same drug as an adult. The proposed studies will focus on unique aspects of neurotransmitter modulation of developmental processes that can lead to long-term molecular and functional defects in gene expression and test whether drug- or genetically-induced changes in DA signaling have different consequences at the molecular level. In order to accomplish this, we propose two aims that will utilize cDNA microarrays to define fundamental, short- and long-term transcriptional adaptations that are the result of exposure to cocaine during pregnancy. We have already used these methods in our laboratory for the study of schizophrenia in human postmortem tissue and recently completed a preliminary microarray experiment comparing gene expression patterns in the striatum from normal and cocaine- exposed fetuses. The data demonstrated very specific differences in gene expression. Aim 1 will focus on changes in genes encoding neuronal signaling and neural development-related molecules following prenatal cocaine exposure. We will focus particularly on the DA-rich anterior cingulate cortex and striatum, regions that exhibit D1 signaling defects. Initial findings will be extended to specialty chips that we will assemble, which contain a large complement of genes encoding neurotransmitter and general cell signaling proteins, and proteins involved in regulating neuronal growth. We will utilize hierarchical analysis of gene groups to assess the possibility that combinations of functionally related genes may be co- modulated due to drug exposure. As in our previous work, the most robustly changed genes will be verified independently by tissue in situ hybridization. This will also allow us to examine regional and cell-type specific changes in transcript expression in brain subregions, such as the nucleus accumbens. Aim 2 will assess the differences in gene expression that arise due to genetic deletion of DA receptor signaling. We focus here on the D1 receptor null mouse because of the similarities in altered cortical development between the genetic mutant and the cocaine- exposed rabbit model. Again, we will use specialty chips to interrogate gene families in more detail. The results of these studies will have significant implications for improving the design of intervention strategies in the population of children prenatally exposed to cocaine and other drugs of abuse that can modulate neurotransmission in the developing nervous system.